Synthesis and powder preparation of fluticasone propionate

ABSTRACT

An improved process for preparing fluticasone propionate, performed in the presence of water, is disclosed. Further disclosed is a process for preparing a fluticasone propionate that is highly suitable for administration by inhalation. Further disclosed are fluticasone propionate and a powdered fluticasone propionate prepared by these processes and pharmaceutical compositions for administration by inhalation containing same. A process of purifying a key intermediate in the synthesis of fluticasone propionate is also disclosed.

RELATED PATENT APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 60/581,702, filed Jun. 23, 2004, and of U.S. ProvisionalPatent Application No. 60/623,877, filed Nov. 2, 2004, the teachings ofwhich are incorporated herein by reference in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to an improved process of preparingfluticasone propionate. The present invention further relates to aprocess of preparing a dry powder form of fluticasone propionate, whichis highly suitable for pharmaceutical formulations.

(S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate), also known and referred toherein and in the art as fluticasone propionate, is a steroidalanti-inflammatory agent of the glucocorticoid family. Fluticasonepropionate is a synthetic corticosteroid which is related to thenaturally-occurring steroid hormone cortisol (hydrocortisone), producedby the adrenal glands. Fluticasone propionate is known as a potent agentfor the treatment of inflammatory respiratory disorders such as asthma,perennial rhinitis and of topical inflammatory conditions.

Fluticasone propionate is marketed worldwide under brand names such asFlovent™, Advair Diskus™, Flonase™, Cutivate™, Atemur™, Flutide™,Flutivate™ and Viani™.

This compound was first disclosed in U.S. Pat. No. 4,335,121. Accordingto the teachings of this patent, fluticasone propionate is prepared viaa multi-step process, which is highly inefficient, resulting in about50% yield. The process taught in this patent is further limited by theuse of expensive reagents such as silver fluoride, which is used forhalide exchange from chloride to fluoride, and cumbersome conditionssuch as dark environment, which renders it inadequate for a preparationin commercial scale.

U.S. Patent Application having the Publication No. 2004/0116396 andIsraeli Patent IL 109,656, which are incorporated by reference as iffully set forth herein, teach an improved process of preparingfluticasone propionate. According to the teachings of these documents,fluticasone propionate can be obtained by the direct esterification ofthe thiocarboxylic acid(6S,9R,10S,11S,13S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioicS-acid (Compound I), with a halofluoromethane, such aschlorofluoromethane, bromofluoromethane and iodofluoromethane, in thepresence of a base, and optionally in the presence of a phase transfercatalyst such as tetrabutylammonium bromide, in an appropriate organicsolvent, as is presented in Scheme 1 below.

This process, however, is highly disadvantageous since the product isobtained in poor yields of 55-60%. In addition, the purity of theobtained product is relatively low and inadequate for pharmaceuticaluse. The obtained product contains a substantial amount of impurities,which is higher than the allowed level of impurities for apharmaceutical product. Thus, additional laborious and costlypurification steps are required in order to provide a product that has apharmaceutically acceptable level of impurity.

There is thus a widely recognized need for, and it would be highlyadvantageous to have, an improved process of preparing fluticasonepropionate in high yields and purity, which is safe, efficient andapplicable to large scale manufacture.

As is mentioned hereinabove, fluticasone propionate is mainly used inthe treatment of inflammatory respiratory disorders such as asthma.Fluticasone propionate is therefore aimed at entering the respiratorytract and reducing the inflammation which causes spasms that narrow theairways.

As a drug which is mainly used for the treatment of respiratorydisorders, the typical mode of administration of fluticasone propionateis by inhalation. Administration by inhalation is most commonly affectedby devices such as dry powder inhalers (DPI) and metered-dose inhalers(MDI) and mostly involves administration of a powdered form of the drug.

Thus, corticosteroids such as fluticasone propionate, as well as otherdrugs formulated and intended for administration by inhalation forpulmonary treatment are required to have a particular particle size andparticle size distribution, in order to obtain an effective therapeuticactivity. On the one hand particles should be small enough to penetratethe lungs, since inadequately large particles will not reach theirtarget bodily sites and cavities, and on the other hand too smallparticles are not desired since they deliver a suboptimal local dosagewhich will not treat the condition effectively at that site.

Typically, the desired particles size of a drug for inhalation is about1-10 microns, and even 1-5 microns, whereby the desired particles sizedistribution is such that minimal amounts of particles sized below 1micron and above 5 microns are present. Such a particle sizedistribution can be achieved by mechanical pulverization techniques suchas milling and micronization. As is well known in the art, milling is acollective term used to describe solid pulverization techniques whichtypically afford relatively large particles sizes, e.g., greater than 10microns, whereby micronization is a collective term used to describesolid pulverization techniques which typically afford relatively smallparticles size. Apart from the particles size, other desiredcharacteristics of a dry powder, delineated hereinafter, are alsoaffected by the drying and milling or micronization processes.

When formulated for administration by inhalation as dry powders, drugsshould further have additional characteristics which are extremelyimportant for their efficient therapeutic use. These include, forexample, shape, morphology, surface properties and electrostatic charge.The particles shape can be polygonal, cylindrical, spherical or oval;the morphology can be amorphous or crystalline; the surface of theparticles can be smooth or rough, and accordingly has lower or higherarea. The particles may further carry an electrostatic charge whichstems from the milling and/or micronizing technique, chemical propertiesof the particular milling and/or micronizing substrate and environmentalconditions.

The shape of the particles affects two major traits which are importantin dry powder modes of therapeutic administration: dry powder flow andthe tendency for agglomeration, wherein the powder flow is beneficialand the tendency for agglomeration is detrimental. The free flowing andtendency for agglomeration characteristics of a substance, as well asthe surface area thereof, are oftentimes affected by the surfacemorphology of the particles.

Thus, when intended for use in the treatment of respiratory disorders,fluticasone propionate in a dry powder form desirably has the followingcharacteristics: high purity, a crystalline form, a well defined, narrowparticle size distribution ranging essentially between 1-5 microns, andfree flowing with minimal tendency to aggregate to larger particles. Inaddition, spherical particles are preferred due to the roughness oftheir surface, which leads to increased separation space betweenparticles, thus preventing agglomeration. Particles devoid of anelectrostatic charge are further preferred since such a charge mayaffect the tendency for agglomeration and may also present safetyhazards and difficulties in the packaging process in bulk manufacturingscale.

While the desired particles size of fluticasone propionate and otherdrugs that are intended for administration by inhalation can be achievedby micronization, this process typically generates particles having asubstantially amorphous surface. Amorphous substances are typicallydisadvantageous due to the relatively high susceptibility thereof tounwanted moisture absorption, which may affect their surface area andfree following characteristics, in comparison to crystalline substances.

In addition, the effectiveness of the micronization process is sensitiveto the hardness of the crystals and therefore it may be difficult toreduce the particle size of some substances below a certain size.Attempts to further reduce the particle size in such cases willtypically result in broadening of the particles size distribution due tothe formation of more hyperfine particle instead of reduction of themedian diameter.

The most widely used milling and/or micronization techniques, whenapplied on drugs, are typically associated with a rather limited abilityto control the abovementioned product characteristics (Malcolmson andEmbleton, Pharm. Sci. Technol., (1998), 1,394-398) and sometimes poseother limitations on the formulation process of drugs.

For example, common mechanical milling and micronization processesoftentimes involve physical contact of the crude drug with metallic orpolymeric objects in order to achieve the reduction of particle size.This contact, which involves abrupt heat generation due to friction maypromote and enhance chemical reaction between the drug and ambientchemicals, such as oxygen and the drug itself, which may lead tochemical modifications of the drug during and after the milling process(Kaneniwa and Ikekawa, Chem. Pharm. Bull., (1972), 20, 1536-1543).

Furthermore, the requirement of a narrow distribution of particle sizeis difficult or impossible to achieve with mechanical millingtechniques. The most common milling technique used for obtainingparticles having an average size in the range of 1-10 microns is air jetmilling. However, this technique does not allow sufficient control ofthe abovementioned product characteristics (Malcolmson and Embleton,Pharm. Sci. Technol., (1998), 1,394-398). In addition, particlesmicronized by air jet milled exhibit a broad particle size distribution(Muller et al., Control Rel. Bioact. Mater. (1996), 22, 574-575). Thetypical broad particle size distribution of an air jet milled powder iscaused by the need to keep the milling process going until the largestparticles fall within the maximum size requirements while the particleswhich already reached that size are excessively milled.

The surface morphology of a mechanically micronized crystalline particleis also difficult, and sometimes impossible, to control. When a directmechanical force is applied on a large crystalline particle, themicronization is controlled by crystal cleavage. Crystal cleavage isdefined as a smooth break along the plane of a lattice layer whichproduces a flat smooth face. Thus, crystal cleavage typically occurs atthe crystal face with the lowest attachment energy, i.e., the mostbrittle direction of the lattice (Roberts, et al. J. Mater. Sci. (1994),29, 2289-2296). The high-energy input required to reduce the particlesize against the relative high crystal lattice free energy (Ogura andSobue, J. Appl. Polymer Sci., (1970), 14, 1390-1393), substantiallyreduces the efficiency of the mechanical micronization process (Parrott,Encyclopedia of pharmaceutical technology, 1990, vol. 3, 101-121). Inaddition, a flat-flake or elongated-rod shaped particles with hightendency to agglomerate and clog are typically obtained.

The use of the presently common mechanical milling processes forobtaining drug powders is further limited by its adverse effect on otherphysical properties of the formed particles. Mechanical millingprocesses oftentimes lead to the formation of a thermodynamicallyactivated surface, and thus alters the surface properties and, as aresult, the physical properties of the drug. Thus, for example,crystalline solid surfaces are typically uncontrollably converted topartially amorphous (disordered) surfaces during the milling process.The resulting disordered surface adversely affects properties such asthe free flowing of the powders. In addition, common mechanical millingprocesses may result in particles with higher and irregular surfacearea, which are further characterized by a higher tendency to accumulateelectrostatic charge, as a result of the mechanical friction andmorphology of the particles. Electrostatically charged powders typicallyexhibit poorer flow properties and high tendency for agglomeration dueto high particulate cohesion forces (Mackin et al., Int. J. Pharm.(2002), 231, 213-226). In view of the limitations associated withmechanical milling and/or micronization processes, alternativetechniques for preparing a dry powder form of a drug, which would besuitable for treating respiratory disorders, have been developed.

U.S. Pat. No. 6,406,718, for example, describes a process for thepreparation of fluticasone propionate having a specific particle sizedistribution and specific dynamic bulk density properties. The processtaught in this patent involves a special technique that utilizessupercritical fluids, and the product is obtained as a novel crystallineform. This process, however, is limited by its high operational costsand complexity, and is further limited by inefficient control of some ofthe important properties mentioned hereinabove, e.g., parcel morphologyand uniformity.

U.S. Patent Application having the publication No. 2004/0081626describes a process for producing powders of pharmaceutically activeagents, including fluticasone propionate, suitable for administration byinhalation. According to the teachings of this patent application, thedrug powder is obtained as crystalline spherical particles. The processis effected by providing a solution of the drug in a liquid carrier,followed by atomizing the liquid carrier into droplets by spraying andsuspending the droplets while heat drying is effected. According to theteachings of U.S. Application 2004/0081626, the process clearly differsfrom conventional spray drying processes since the atomization of thefeedstock is performed in a separate part of the device and the mistflows into a heating chamber where the solvent in the droplets isvaporized, while in the conventional spray drying device the atomizationand heating is afforded by the same factor which is the hot gas streamaiding in the atomization stage, suspend the mist, heats and evaporatethe solvent in one chamber. This process is therefore limited bycomplexity of the technique utilized thereby and further by thecontinuous exposure of the drug to heat throughout the drying process.

U.S. Patent Application having the publication No. 2001/0046474 and WO99/16419 both describe a process for producing powders ofpharmaceutically active agents, including fluticasone propionate,suitable for administration by inhalation. These patent applicationsteach the preparation of powders having hollow porous micro-sphericalparticles by providing a solution of the drug in a liquid carrier,atomizing the liquid carrier solution into droplets, suspending thedroplets and spray-drying the resulting emulsion in the presence ofphospholipid surfactants. Again, this process is limited by itscomplexity and is further disadvantageous due to the presence ofphospholipid surfactants during the spray-drying process. Such additivesare hard to remove from the final product and their presence may affectthe purity of the final product.

WO 01/58425 describes a process for producing powders ofpharmaceutically active agents, including fluticasone propionate,suitable for administration by inhalation. The process taught in thisapplication involves dissolving the drug in water, adding a vinylpolymer such as poly(vinyl)alcohol (PVA) to the aqueous solution andspray-drying the solution by conventional spray-drying techniques.Again, this process is disadvantageous due to the presence of anadditive such as PVA, which may affect the pharmaceutical purity of thefinal product and/or requires the use of larger amounts of the finalproduct, such that overall using such an additive increases the cost ofthe drug's production and formulation.

U.S. Pat. No. 6,221,398 describes a process for producing powders ofpharmaceutically active agents, including fluticasone propionate,suitable for administration by inhalation. According to the teachings ofthis patent, powders that contain crystalline particles of a drug areproduced by dissolving the drug in a liquid solvent and transferring thesolution as a jet stream into an anti-solvent, which is miscible withthe solvent, followed by spray drying. This process thus requires acomplicated technique, which utilizes a complexed solvent system and istherefore disadvantageous for use in an industrial scale.

WO 98/29096 describes a process for producing powders ofpharmaceutically active agents, including fluticasone propionate,suitable for administration by inhalation. The process taught in thisapplication is effected by dissolving the drug in acetone or ethanol,followed by the addition of an aqueous solution of lactose andsimultaneous spray-drying of the combined solutions. This process isdisadvantageous due to the presence of an additive such as lactose,which requires the use of larger amounts of the final product, andoverall leads to increased cost of the drug's production andformulation.

In a recently published article (H. Steckel, N. Rasenack, P. Villax andB. W. Muller, International Journal of Pharmaceutics, 258, (2003),65-75), a process for the preparation of fluticasone propionate thathave special particle size distribution in the micron region isdescribed. According to the teachings of this publication, suchparticles are obtained by dissolving the substance in acetone andprecipitating it by a solvent change method in the presence of celluloseether, such as hydroxypropylmethyl-cellulose, as a stabilizinghydrocolloid (gel). By rapidly pouring the drug solution into thepolymer-rich water phase, the previously molecularly dispersed drug isassociated to small particles and is simultaneously stabilized againstcrystal growth by the hydrophilic polymer. The resulting dispersion isthen spray dried to give solid particles of fluticasone propionate.Still, this process involves a complicated technology and is furtherlimited by the use of a substance that may affect the pharmaceuticalpurity of the final product and/or requires the use of larger amounts ofthe final product, such that overall using such a technology results incost-inefficiency of the drug's production and formulation.

In summary, the presently known methods and techniques for obtainingfluticasone propionate which is suitable for administration byinhalation, and thus can be used in the treatment of disorders in therespiratory tract, are limited either by the physical characteristics ofthe obtained product, by using expensive and complicated machinery,techniques and chemicals, and/or by mixing the pure substance withadditives.

There is thus a widely recognized need for, and it would be highlyadvantageous to have, a process for obtaining a dry powder form offluticasone propionate suitable for administration by inhalation, devoidof the above limitations.

SUMMARY OF THE INVENTION

The present inventors have now surprisingly found that fluticasonepropionate can be efficiently prepared by reacting the thiocarboxylicacid, Compound I with a halofluoromethane, in the presence of water. Thepresent inventors have further found, surprisingly, that a powderedfluticasone propionate, which is highly suitable for administration byinhalation can be obtained using a conventional spray drying technique,while avoiding the use of additives.

Thus, according to one aspect of the present invention there is provideda process of preparingS-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate(fluticasone propionate), which comprises: providing6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; reacting the6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid with a halofluoromethane in the presence of an organic solvent,water and a base, to thereby obtain a reaction mixture containingfluticasone propionate; and isolating the fluticasone propionate fromthe reaction mixture, thereby obtaining the fluticasone propionate.

According to further features in preferred embodiments of the inventiondescribed below, the halofluoromethane is selected from the groupconsisting of chlorofluoromethane, bromofluoromethane andiodofluoromethane.

According to still further features in the described preferredembodiments the organic solvent is selected from the group consisting oftetrahydrofuran, 2-methyltetrahydrofurane, acetonitrile and any mixturethereof.

According to still further features in the described preferredembodiments the base is a tertiary alkylamine.

According to still further features in the described preferredembodiments the amount of the water ranges from about 1 weight percentto about 200 weight percents, more preferably from about 40 weightpercents to about 70 weight percents, of the weight of the6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid.

According to still further features in the described preferredembodiments the process further comprises, prior to the reacting,purifying the6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid.

According to still further features in the described preferredembodiments the purifying the6α,9α-difluoro-11β-hydroxy-17β-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid comprises:

-   -   providing a solution of the        6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17′-thiocarboxylic        acid and an organic solvent;    -   contacting the solution with an aqueous solution containing a        base, to thereby provide an aqueous solution containing a base        addition salt of the        6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17α-thiocarboxylic        acid;    -   isolating the aqueous solution containing the base addition        salt;    -   converting the base addition salt into the        6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylic        acid; and    -   isolating the        6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylic        acid, to thereby provide a purified        6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylic        acid.

According to still further features in the described preferredembodiments the fluticasone propionate has a purity that equals to or isgreater than 99%, preferably equals to or is greater than 99.5%.

According to still further features in the described preferredembodiments the process further comprises, subsequent to the isolating:providing a powdered fluticasone propionate, preferably by subjectingthe fluticasone propionate to spray drying.

According to still further features in the described preferredembodiments the spray drying comprises: providing a solution containingfluticasone propionate and a solvent; and spray drying the solution.

According to still further features in the described preferredembodiments the solution is substantially devoid of an additive.

According to still further features in the described preferredembodiments there are provided fluticasone propionate and powderedfluticasone propionate, prepared as described above.

According to another aspect of the present invention there is providedfluticasone propionate that has a purity that equals to or is greaterthan 99%, preferably that equals to or is greater than 99.5%.

According to still another aspect of the present invention there isprovided a process of preparing a powdered fluticasone propionate, whichcomprises: providing fluticasone propionate; dissolving the fluticasonepropionate in a solvent to thereby obtain a solution containing thefluticasone propionate, the solution being substantially devoid of anadditive; and spray drying the solution, thereby obtaining the powderedfluticasone propionate.

According to further features in preferred embodiments of the inventiondescribed below, providing the fluticasone propionate is effected by theprocess described hereinabove.

According to still further features in the described preferredembodiments the powdered fluticasone propionate has at least onecharacteristic selected from the group consisting of: an average sizethat ranges from about 1 micron to about 10 micron; free flowing; asubstantially spherical particles shape; and a substantial absence of anelectrostatic charge.

According to still further features in the described preferredembodiments the powdered fluticasone propionate is substantiallycrystalline.

According to still further features in the described preferredembodiments the powdered fluticasone propionate is partially amorphous.

According to still further features in the described preferredembodiments the average particle size of the powdered fluticasonepropionate ranges from about 1 micron to about 5 microns.

According to still further features in the described preferredembodiments a particle size of at least 90 percents of the particles ofthe powdered fluticasone propionate ranges from 1 to 5 microns.

According to still further features in the described preferredembodiments a particle size of about 50 percents of the particles of thepowdered fluticasone propionate ranges from about 2 microns to about 3microns.

According to still further features in the described preferredembodiments a particle size of about 50 percents of the particles of thepowdered fluticasone propionate ranges from about 3 microns to about 5microns.

According to still further features in the described preferredembodiments the solvent is selected from the group consisting of analcohol, a ketone and a mixture thereof.

According to still further features in the described preferredembodiments the alcohol is selected from the group consisting of ethanoland isopropanol.

According to still further features in the described preferredembodiments the ketone is selected from the group consisting of acetoneand methyl ethyl ketone.

According to still further features in the described preferredembodiments a ratio between the alcohol and the ketone in the mixture isabout 1:1.

According to still further features in the described preferredembodiments the spray drying is performed at an outlet temperaturegreater than 60° C.

According to still further features in the described preferredembodiments the spray drying is performed at a flow of about 50 m³/hour.

According to still further features in the described preferredembodiments there is provided a powdered fluticasone propionate preparedby the process described hereinabove.

According to yet another aspect of the present invention there isprovided a powderedS-fluoromethyl-6α9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate(fluticasone propionate) being characterized by at least onecharacteristic selected from the group consisting of: an averageparticle size that ranges from about 1 micron to about 10 micron,preferably from about 1 micron to about 5 microns; free flowing; asubstantially spherical particles shape; and a substantial absence of anelectrostatic charge.

According to further features in preferred embodiments of the inventiondescribed below, the powdered fluticasone propionate is substantiallycrystalline.

According to still further features in the described preferredembodiments the powdered fluticasone propionate is partially amorphous.

According to still further features in the described preferredembodiments a particle size of at least 90 percents of the particles ofthe powdered fluticasone propionate ranges from 1 to 5 microns.

According to still further features in the described preferredembodiments a particle size of about 50 percents of the particles of thepowdered fluticasone propionate ranges from about 2 microns to about 3microns.

According to still further features in the described preferredembodiments a particle size of about 50 percents of the particles of thepowdered fluticasone propionate ranges from about 3 microns to about 5microns.

According to still further features in the described preferredembodiments there is provided a pharmaceutical composition formulatedfor administration by inhalation, which comprises the powderedfluticasone propionate described herein.

According to an additional aspect of the present invention there isprovided a process of purifying6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid, which is effected essentially as described hereinabove.

The present invention successfully addresses the shortcomings of thepresently known configurations by providing a novel, yet simple, processof preparing highly pure fluticasone propionate in high yield and anovel, yet simple, process of preparing a dry powder form of fluticasonepropionate, which is highly suitable for use in administration beinhalation.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In case of conflict, the patentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

As used herein the term “mixture” describes a mixture that includes morethan one substance and which can be in any form, for example, as ahomogenous solution, a suspension, a dispersion, a biphasic system andmore.

As used in this application, the singular form “a,” “an,” and “the”include plural references unless the context clearly dictates otherwise.For example, the term “an agent” includes a plurality of agents,including mixtures thereof.

Throughout this disclosure, various aspects of this invention can bepresented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

As used herein throughout, the term “comprising” means that other stepsand ingredients that do not affect the final result can be added. Thisterm encompasses the terms “consisting of” and “consisting essentiallyof”.

The phrase “consisting essentially of” means that the composition ormethod may include additional ingredients and/or steps, but only if theadditional ingredients and/or steps do not materially alter the basicand novel characteristics of the claimed composition or method.

The term “method” or “process” refers to manners, means, techniques andprocedures for accomplishing a given task including, but not limited to,those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin the cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice.

In the drawings:

FIG. 1 presents a micrograph of a sample of powdered fluticasonepropionate micronized by a standard air-jet milling technique aspresented in Reference Example 12 in the Examples section that follows,showing the irregular jaggedly shape of the particles produced by thistechnique;

FIG. 2 presents the dynamic light scattering measurement performed forpowdered fluticasone propionate prepared according to Example 13,showing the particles size distribution as the average size of particlesper percentile, denoted as D, and demonstrating the narrow and welldefined distribution of the particles, with D(0.10) of 0.95 micron,D(0.20) of 1.31 micron, D(0.50) of 2.21 microns, D(0.80) of 3.43microns, D(0.90) of 4.23 microns, D(0.95) of 4.96 microns, D(0.98) of5.82 microns, D(0.99) of 6.37 microns and D(1.00) of 8.11 microns;

FIG. 3 presents the X-ray power diffraction spectrum measured forpowdered fluticasone propionate prepared according to Example 13,showing a discrete (spiky) character typical to a powder havingparticles with high content of well-ordered morphology, demonstratingthe crystalline morphology of the particles produced by this process ofthe present invention;

FIG. 4 presents a SEM micrograph of a sample of powdered fluticasonepropionate as prepared according to an exemplary process according tothe present embodiments (as detailed in Example 13), showing the uniformspherical shape of the particles which contribute to the free-flowingcharacter of the resulting powder;

FIG. 5 presents the dynamic light scattering measurement performed forpowdered fluticasone propionate prepared according to Example 14,showing the particles size distribution as the average size of particlesper percentile, denoted as D, and demonstrating the narrow and welldefined distribution of the particles, with D(0.10) of 0.96 micron,D(0.20) of 1.27 micron, D(0.50) of 2.14 microns, D(0.80) of 3.44microns, D(0.90) of 4.36 microns, D(0.95) of 5.27 microns, D(0.98) of6.44 microns, D(0.99) of 7.32 microns and D(1.00) of 13.54 microns;

FIG. 6 presents the dynamic light scattering measurement performed forpowdered fluticasone propionate prepared according to Example 15,showing the particles size distribution as the average size of particlesper percentile, denoted as D, and demonstrating the narrow and welldefined distribution of the particles, with D(0.10) of 1.06 micron,D(0.20) of 1.52 micron, D(0.50) of 2.67 microns, D(0.80) of 4.51microns, D(0.90) of 5.95 microns, D(0.95) of 7.51 microns, D(0.98) of9.81 microns, D(0.99) of 11.67 microns and D(1.00) of 2000.00 microns;

FIG. 7 presents the dynamic light scattering measurement performed forpowdered fluticasone propionate prepared according to Example 16,showing the particles size distribution as the average size of particlesper percentile, denoted as D, and demonstrating the narrow and welldefined distribution of the particles, with D(0.10) of 1.90 micron,D(0.20) of 2.46 microns, D(0.50) of 4.11 microns, D(0.80) of 6.70microns, D(0.90) of 8.40 microns, D(0.95) of 9.86 microns, D(0.98) of11.35 microns, D(0.99) of 12.10 microns and D(1.00) of 14.24 microns;and

FIG. 8 presents the X-ray power diffraction spectrum measured forpowdered fluticasone propionate prepared according to Example 16,showing a relatively continuous smooth (curve) character typical to apowder having particles with amorphous morphology and low level ofcrystallinity, demonstrating the mostly amorphous morphology of theparticles; and

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of (i) a novel process of preparing fluticasonepropionate in high yield and purity; (ii) highly pure fluticasonepropionate prepared by this process; (iii) a novel process of preparinga powdered fluticasone propionate which is highly suitable foradministration by inhalation; (iv) a powdered fluticasone propionateprepared by this process; and (v) pharmaceutical compositions containingthe fluticasone propionate and the powdered fluticasone propionatedescribed above. The present invention is further of a process ofpurifying6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid, a key intermediate in the synthesis of fluticasone propionate.

The principles and operation of the present invention may be betterunderstood with reference to the drawings and accompanying descriptions.

As discussed in detail hereinabove, fluticasone propionate is a highlypotent agent for the treatment of inflammatory respiratory disorderssuch as asthma, perennial rhinitis and of topical inflammatoryconditions and is marketed worldwide.

As is further discussed in detail hereinabove, the presently knownprocesses for preparing fluticasone propionate are limited, inter alia,by poor chemical efficiency, which lead to poor yield and purity of thefinal product.

In a search for an improved process of preparing fluticasone propionate,the present inventors have now surprisingly found that fluticasonepropionate can be efficiently prepared in the presence of water.Specifically, it was found that fluticasone propionate can be preparedby reacting6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid (which is also referred to herein interchangeably Compound I orsimply as thiocarboxylic acid) with a halofluoromethane, in the presenceof water and a base, in an appropriate organic solvent. It was furtherfound that fluticasone propionate thus prepared can be readily isolatedfrom the reaction mixture and is obtained in higher yield and purity ascompared with the prior art processes. Such a process is highlyapplicable for industrial scale-up and is further beneficial since itresults in fluticasone propionate having a pharmaceutical purity.

As used herein and in well accepted in the art, the phrase“pharmaceutical purity” of a substance (e.g., fluticasone propionate)describes a substance that has purity characteristics that conform todrug regulations assuring that the substance meets the requirements ofthe act as to safety and meets the quality it is represented to possess.Typically, a substance (e.g., drug) having a pharmaceutical purity is asubstance having less than 0.50% by weight total content of impurities.

Thus, according to one aspect of the present invention there is provideda process of preparing fluticasone propionate. The process, according tothis aspect of the present invention is effected by providing thethiocarboxylic acid Compound I (see, Schemes 1 and 2); reacting thethiocarboxylic acid with a halofluoromethane in the presence of waterand a base, to thereby obtain a reaction mixture containing fluticasonepropionate; and isolating the fluticasone propionate from the reactionmixture.

The process according to this aspect of the present invention isillustrated in Scheme 2 below.

The thiocarboxylic acid (Compound I) used as the starting material inthis process is known and obtainable by conventional methods known inthe art, such as, for example, those described in U.S. PatentApplication having the Publication No. 2004/0116396 and Israeli PatentIL 109,656.

According to a preferred embodiment of this aspect of the presentinvention, the thiocarboxylic acid is further purified prior to thereaction with the halofluoromethane.

The present inventors have now surprisingly found that thethiocarboxylic acid can be efficiently and easily purified by convertingit to the base addition salt thereof and then re-converting the baseaddition salt to the free acid. As is exemplified in the Examplessection that follows, such a purification process is effected in highyield.

Thus according to preferred embodiments of this aspect of the presentinvention and further according to another aspect of the presentinvention, there is provided a process of purifying6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid (Compound I), which is generally effected by: providing thethiocarboxylic acid Compound I, using any of the methods known in theart; converting the thiocarboxylic acid into a base addition saltthereof, converting the base addition salt into the free thiocarboxylicacid; and isolating the thus obtained thiocarboxylic acid. Preferably,the base addition salt of the thiocarboxylic acid is isolated prior toits conversion to the free acid form.

Converting the thiocarboxylic acid into the base addition salt thereofcan be performed by reacting the compound with a base, preferably anaqueous solution of a base, in the presence of an organic solvent.

Thus, converting the thiocarboxylic acid into the base addition saltthereof can be performed by contacting a solution containing thethiocarboxylic acid and an organic solvent with an alkaline aqueoussolution, namely an aqueous solution that contains a water-soluble base.

The base used in these embodiments of the present invention is thereforepreferably a water soluble base and can be an inorganic base or anorganic base.

More preferably, the base is an inorganic base such as, but not limitedto, sodium hydroxide, sodium carbonate, potassium carbonate, sodiumbicarbonate and the like. Preferably, the base is sodium bicarbonate.

Thus, the base addition salt of the thiocarboxylic acid formed in thisprocess can be, for example, a sodium addition salt, a potassiumaddition salt and the like.

The conversion of the thiocarboxylic acid to the base additional saltthereof is performed in a biphasic system comprised of an aqueous phasecontaining the base and an organic solvent, in which the thiocarboxylicacid (in its preliminary free form) is dissolved. Once thethiocarboxylic acid reacts with the base, the formed base addition saltis present within the aqueous phase of the biphasic system and thus canbe easily separated from the reaction mixture.

Using such a biphasic system allows for an efficient isolation of thewater-soluble base addition salt from the reaction mixture whilewater-insoluble impurities remain in the organic phase.

Converting the base addition salt of the thiocarboxylic acid in its freeform is preferably performed by reacting it with an acid, preferablywith an aqueous solution of an acid and more preferably with an aqueoussolution of an inorganic acid such as HCl. This conversion is preferablyeffected while adjusting the pH of this reaction mixture to a pH lowerthan 4, more preferably lower than 3, and more preferably, to a pH ofabout 1-2.

The thus formed purified free thiocarboxylic acid is obtained as aprecipitate, which is easily separated from the reaction mixture bye.g., filtration. The separated purified thiocarboxylic acid can befurther dried using conventional drying procedures.

As is exemplified in the Examples section that follows, using thepurification process described above, purified thiocarboxylic acid isobtained in high yield (e.g., greater than 80%) and high purity (e.g.,95.7%, as determined by HPLC).

When used as a starting material in the process of preparing fluticasonepropionate presented herein, the thiocarboxylic acid may be either in adry form or in a wet form, as is detailed hereinbelow.

Turning back to the process of preparing fluticasone propionateaccording to the present embodiments, once the thiocarboxylic acid isprovided, it is reacted with a halofluoromethane, represented as XFCH₂,wherein X can be chloro, bromo or iodo, in Scheme 2 above.

Thus, the halofluoromethane utilized in the process according of thisaspect of the present invention can be, for example,chlorofluoromethane, bromofluoromethane and iodofluoromethane, and ispreferably chlorofluoromethane.

In a preferred embodiment of this aspect of the present invention, anexcessive molar amount, relative to the thiocarboxylic acid, of thehalofluoromethane is used in this process. Preferably, the relativeamount of the halofluoromethane ranges from about 1 molequivalent toabout 10 molar equivalents relative to the molar amount of thethiocarboxylic acid, more preferably from about 1 molequivalent to about5 molequivalents and most preferably from about 2 molequivalents toabout 4 molequivalents, relative to the molar amount of thethiocarboxylic acid.

As used herein throughout, the term “about” refers to ±10%.

According to a preferred embodiment of this aspect of the presentinvention, reacting the thiocarboxylic acid with the halofluoromethaneis performed in an organic solvent.

Since the process described herein is performed in the presence ofwater, suitable organic solvents for use in this context of the presentinvention are water-miscible solvents such as, but not limited to,alcohols, ethers, nitriles, amides, ketones, sulfoxides and the like,including any combination thereof.

Non-limiting examples of water miscible organic solvents that are usablein the context of the present invention therefore include, alcohols suchas, but not limited to, methanol, ethanol, propanol, isopropyl alcohol,butanol, isobutanol, t-butanol, pentanol, hexanol, cyclohexanol, andbenzyl alcohol; cyclic ethers, such as, but not limited to,tetrahydrofuran, 2-methyltetrahydrofurane, pentamethylene oxide,1,4-dioxane and the like, amides such as, but not limited to,N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide,sulfolane, 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-oxazolidone,1,3-dimethyl-2-imidazolidinone, acetonitrile, and acetone. Thesesolvents may be used either individually or as a combination of two ormore of the foregoing.

More preferred solvents that are suitable for use in this context of thepresent invention include, without limitation, tetrahydrofuran,2-methyltetrahydrofurane, acetonitrile, and any combination thereof. Thepresently most preferred solvent is acetonitrile.

Reacting the thiocarboxylic acid with the halofluoromethane is performedin the presence of a base.

The base can be an inorganic base or an organic base.

Non-limiting examples of inorganic bases that are suitable for use inthis context of the present invention include, without limitation, metalhydroxides such as sodium hydroxide and potassium hydroxide; metalcarbonates such as sodium carbonate and potassium carbonate; and metalhydrogencarbonates such as sodium hydrogencarbonate and potassiumhydrogencarbonate (also referred to herein as in the art as sodiumbicarbonate and potassium bicarbonate, respectively) or a combinationthereof.

Non-limiting examples of organic bases that are suitable for use in thiscontext of the present invention include, without limitation, tertiaryalkylamines such as triethylamine, tributylamine andN,N-diisopropylethylamine; dialkylanilines such as N,N-dimethylanilineand N,N-diethylaniline; heterocyclic amines such as pyridine,N,N-dimethylaminopyridine and N-methylmorpholine;1,8-diazobicyclo[5,4,0]undecene, N-benzyltrimethylammonium hydroxide andany combination thereof.

Preferably, the base is an organic base and more preferably it is atertiary alkylamine such as triethylamine, tributylamine andN,N-diisopropylethylamine, whereby the presently most preferred base isN,N-diisopropylethylamine.

The amount of the base used in this process of the present inventionpreferably ranges from about 0.1 molequivalent to about 15molequivalents relative to the thiocarboxylic acid, more preferably fromabout 1 molequivalent to about 10 molequivalents relative to thethiocarboxylic acid, and more preferably from about 1 molequivalent toabout 5 molequivalents relative to the thiocarboxylic acid.

As discussed hereinabove, the process according to this aspect of thepresent invention is efficiently performed in the presence of water. Asis demonstrated in the Examples section that follows, the processaccording to this aspect of the present invention was efficientlyperformed in the presence of variable amounts of water, ranging from 5weight percentages of water relative to the weight of the thiocarboxylicacid to 200 weight percentages of water relative to the weightthiocarboxylic acid used.

The amount of the water used in this process can therefore range fromabout 1 weight percentage to about 200 weight percentages, preferablyfrom about 20 weight percentages to about 100 weight percentages, andmore preferably form about 40 weight percentages to about 70 weightpercentages, relative to the weight of the thiocarboxylic acid.

As mentioned hereinabove, the thiocarboxylic acid utilized in thisprocess of the present invention can be either is a dry form or is a wetform.

When utilized in a dry form, reacting the thiocarboxylic acid with thehalofluoromethane in the presence of water is effected by adding thewater to the reaction mixture, whereby the amount of the added water isas described hereinabove. In this case, the process according to thisaspect of the present invention may further be effected by dryingthiocarboxylic acid prior to reacting it with the halofluoromethane,using any of the conventional drying methods known in the art.

When utilized in a wet form, the total amount of the water used whilereacting the thiocarboxylic acid with the halofluoromethane can includethe water content of the thiocarboxylic used. Thus, for example, if thethiocarboxylic acid utilized in the process according to this aspect ofthe present invention is in a wet form, and depending on the desiredtotal amount of water utilized in the process, as is detailedhereinabove, addition of water to the reaction mixture can be avoided.If the water content in the starting material is insufficient, water maybe added directly to the reaction mixture, or may be added initially tothe starting material.

Reacting the thiocarboxylic acid and the halofluoromethane, in thepresence of water and a base, as described hereinabove, can beconveniently performed at room temperature. Optionally and preferably,the reaction is performed at elevated temperatures. Thus, the reactioncan be carried at a temperature that ranges from room temperature andthe reflux temperature of the solvent (or, in the absence of solvent,the reflux temperature of water). Preferably, the reaction is carriedout at a temperature that ranges between 40° C. and 60° C.

Further, the reaction can be conveniently conducted at atmosphericpressure.

Optionally and preferably, the reaction may be carried out in a sealedhigh-pressure reaction vessel, under elevated pressure that may developduring the reaction.

Depending on the reaction conditions, namely, the temperature andpressure, the reaction time required to achieve high conversion of thethiocarboxylic acid to fluticasone propionate may range from 1 hour to afew days. When the reaction is conducted at elevated temperatures, asdetailed hereinabove, and in a sealed reaction vessel, the reaction timepreferably ranges from about 1 hour to about 10 hours, more preferablyfor about 5 hours.

Once the reaction is completed, the obtained fluticasone propionate canbe isolated from the reaction mixture using any of the conventionaltechniques known in the art.

Thus, isolating the fluticasone propionate from the reaction mixture canbe performed using, for example, filtration, centrifugation, extraction,evaporation, trituration, column chromatography, preparative thin-layerchromatography, preparative low, medium or high-pressure liquidchromatography or any combination of thereof, with filtration being thepresently most preferred technique.

Once isolated from the reaction mixture, the fluticasone may optionallybe dried, using conventionally known methods. Thus, drying thefluticasone propionate obtained by the process described herein may becarried out, for example, by increasing the temperature or reducing thepressure or a combination of both. Non-limiting examples of dryingtechnologies or equipments usable in this context of the presentinvention include vacuum ovens, tray ovens, rotary ovens and fluidizedbed dryers.

Using the process described herein, fluticasone propionate is obtainedin high yield and purity.

As is demonstrated in the Examples section that follows, in exemplaryprocesses performed as described herein, fluticasone propionate wasobtained in a yield of about 80%.

Thus, according to an embodiment of this aspect of the presentinvention, using the process described herein, the fluticasonepropionate is obtained in a yield greater than 60%, preferably greaterthan 70%, and more preferably greater than 80%, relative to the molaramount of the thiocarboxylic acid starting material (Compound I).

Such a high yield clearly demonstrates the higher efficiency of thisprocess as compared with the presently known processes for preparingfluticasone propionate described above, in which the product wasobtained in a yield of 50-60%.

As is further demonstrated in the Examples section that follows, inexemplary processes performed as described herein, the purity of theobtained fluticasone propionate was greater than 99% and even greaterthan 99.5% and, in some cases, even greater than 99.8%, before anypurification procedure was applied. As discussed hereinabove, suchpurity corresponds to pharmaceutical purity.

Thus, according to preferred embodiments of this aspect of the presentinvention, using the process described above fluticasone propionatehaving a purity that is equal to or greater than 99%, preferably equalto or greater than 99.1%, more preferably equal to or greater than99.2%, more preferably equal to or greater than 99.3%, more preferablyequal to or greater than 99.4%, and even more preferably equal to orgreater than 99.5%, as determined by HPLC, is obtained.

Thus, using the process described herein fluticasone propionate having apharmaceutically acceptable purity, that is, an impurity content of nomore than 0.5%, can be obtained, without the need to use laboriouspurification procedures.

Notwithstanding the above, once isolated and optionally dried, theobtained fluticasone propionate can be further purified, using any ofthe conventionally known purification procedures. Thus, the fluticasonepropionate can be purified using, for example, extraction, columnchromatography, preparative low-pressure liquid chromatography,preparative high-pressure liquid chromatography, re-crystallization,slurrying and any combination thereof.

In an embodiment of this aspect of the present invention, the minuteamount of impurities present in the product can be removed by treatingthe fluticasone propionate with activated charcoal. The activatedcharcoal can be added to the reaction mixture, once the reaction iscompleted and prior to isolating the product. If desired, a filter-aidmay be additionally added. According to this embodiment, when theactivated charcoal is added to the reaction mixture, stirring iscontinued, preferably at a constant temperature and for a time periodthat ranges from 5 minutes to 60 minutes, preferably from 10 minutes to30 minutes, and most preferably is about 15 minutes, and the resultingmixture is then filtered to remove the solids. The purified fluticasonepropionate may be thereafter dried by any of the drying methodsdescribed hereinabove. Alternatively, the fluticasone propionate can betreated with the activated charcoal subsequent to its isolation, bydissolving the isolated product in an organic solvent and treating theresulting solution with the activated charcoal, as describedhereinabove.

According to another embodiment of this aspect of the present invention,the fluticasone propionate is purified by recrystallization. Preferably,the re-crystallization is carried out from a solvent mixture ofisopropanol and acetone. As is discussed in detail hereinabove, sincefluticasone propionate is a potent agent for treating disorders in therespiratory tract, it is preferably formulated for administration byinhalation. As such, the fluticasone propionate is desirably used in adry powder form which should have a specific particles size andparticles size distribution, as well as other characteristics, as isdiscussed hereinabove and is further detailed hereinbelow.

Thus, the fluticasone propionate prepared by the process describedhereinabove, can be further utilized for providing a powderedfluticasone propionate that is characterized by a desired particles sizeand particles size distribution.

As used herein throughout, the phrase “powdered fluticasone propionate”describes a solid substance (the fluticasone propionate) that is in afinely divided state, namely a particulate substance. In other words,this phrase describes a solid substance in the form of tiny looseparticles.

Providing a powdered fluticasone propionate that is characterized by adesired particles size and particles size distribution can be effectedby subjecting the fluticasone propionate obtained by the processdescribed above to mechanical micronization.

Any of the commonly used methods of mechanical micronization can be usedfor that purpose, including, for example, air jet milling, spiral jetmilling, and fluid bed jet milling.

Other techniques commonly utilized for obtaining particles of thedesired size and size distribution can also be employed. These includesuper-critical fluid processing to form nanoparticles, high pressurehomogenization and spray drying.

Preferably, and as is described in detail hereinbelow, the processdescribed hereinabove further includes spray drying the fluticasonepropionate obtained and more preferably, further includes spray dryingthe obtained fluticasone propionate using the technology described indetail hereinbelow.

Thus, according to further embodiments of this aspect of the presentinvention, there is provided a powdered fluticasone propionate, preparedas described hereinabove.

Using the process according to this aspect of the present invention,highly pure fluticasone propionate, optionally in a powdered form, isobtained in high yield. This process is easy to performed and can bereadily, conveniently and cost-effectively scaled-up. Thus, using theprocess provided herein, industrial preparation of fluticasonepropionate can be efficiently and advantageously performed.

Further according to the present invention there is provided highly purefluticasone propionate. The fluticasone propionate according to thisaspect of the present invention has a purity that is equal to or greaterthan 99%, preferably equal to or greater than 99.1%, more preferablyequal to or greater than 99.2%, more preferably equal to or greater than99.3%, more preferably equal to or is greater than 99.4%, and even morepreferably equal to or greater than 99.5%, as determined by HPLC.

Further according to the present invention, there is provided a novelprocess of preparing a powdered fluticasone propionate that is suitablefor use for administration by inhalation.

As discussed hereinabove, fluticasone propionate is mainly used in thetreatment of inflammatory respiratory disorders such as asthma, andtherefore its main mode of administration is by inhalation. As such,fluticasone propionate is required to comply with several precisequality standards such as maximal and minimal particular particle size,narrow particle size distribution, free flowing flow and a low tendencyto agglomerate. These qualities are affected by several characteristicsof the solid particles, some of which arise from the process by whichthe particles are obtained, and which include particle shape, surfacemorphology and area and the tendency to absorb moisture and accumulatestatic charge.

As mentioned hereinabove, the standard mechanical drug-milling andmicronization techniques, such as air-jet milling, is routinely used forreduction of particle size of powders and for obtaining particle sizedistribution of the powders in the range of 1-10 microns. As air-jetmilling equipment is available from many suppliers, the presentinventors have attempted to apply this particle size reduction techniqueon fluticasone propionate. These attempts, presented in Example 12 inthe Example section that follows, gave unsatisfactory results. Theoverall time-consuming process resulted in a powder which containedeither too many oversized particles or too many undersized particles,and further tended to accumulate a considerable amount of static chargeand generally tended to agglomerate. The present inventors have alsorecorded a significant reduction in the crystallinity of the finalparticles and an irregular shape of the particles, as is shown in theSEM micrograph presented in FIG. 1. Therefore it was concluded thatmechanical air-jet milling techniques are not suitable for fluticasonepropionate as these processes typically result in the disadvantageousirregular and jaggedly shaped particles having an amorphous surface,while failing to achieve the required narrow particle size distributionof 1-10 microns. These undesired powder characteristics might have anegative effect on the therapeutic activity of the drug in therespiratory tract.

In a search for an improved process for obtaining pharmaceuticallyacceptable dry powder form of fluticasone propionate which is suitablefor administration by inhalation, the present inventors have turned tothe well established technique known as spray drying.

Spray drying is the most widely used industrial process involvingparticle formation and drying. It is highly suited for the continuousproduction of dry solids in either powder, granulate or agglomerate formfrom liquid feedstocks such as solutions, emulsions and pumpablesuspensions. Spray drying involves the atomization of a liquid feedstockinto a spray of droplets and contacting the droplets with hot air in adrying chamber until all solvent is evaporated from the droplets. Thesprays are produced by either rotary (wheel) or nozzle atomizers. Theevaporation of the solvent from the droplets and formation of dryparticles proceed under controlled temperature and airflow conditions,and the resulting powder is discharged continuously from the dryingchamber.

The most crucial parts of the spray drying process are the atomizationof the droplets and the evaporation of the solvent. Both processes canbe affected by the type of the liquid carrier used, stemming fromphysical and/or mechanical properties of the carrier such as viscosityand rheological characteristics, boiling point, gas content,hygroscopicity and the like, as well as the solubility of the drug in aparticular liquid carrier. The carrier therefore determines the shapeand size of the droplets, the size distribution and the amount oflingering carrier residual.

The carrier used in a spray drying process aimed at producingwell-defined powders is desirably selected capable of dissolvingrelatively high drug content (high drug solubility in the carrier),having adequate physical and/or mechanical properties so as to allow theformation of small and uniform spherical droplets and high evaporationrate at moderate to low temperatures.

As mentioned above, attempts to apply a conventional spray dryingtechnique to drugs such as fluticasone propionate have met limitedsuccess. Complicated related techniques which utilized eithermulti-phasic conditions, multi-solvent systems and other cost- andtime-consuming processes have been used. Alternatively, conventionalspray drying technique was used while disadvantageously adding variousadditives to the liquid feedstock in order to achieve the requiredsolution properties which lead to the desirable powders properties ofthe drug.

In a search for an industrially applicable and efficient process forpreparing powdered fluticasone propionate that is suitable foradministration by inhalation, the present inventors have nowsurprisingly found that a powdered fluticasone propionate characterizedby the desired properties, as is detailed herein, can be achieved usingthe conventional spray drying technique while circumventing the need touse additives or any other complicated procedures.

Hence, according to further aspects of the present invention, there areprovided a powderedS-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate(fluticasone propionate), as this phrase is defined hereinabove,suitable for administration by inhalation, and a process for obtainingsame.

The process, according to these aspects of the present invention, iseffected by:

-   -   providing fluticasone propionate; dissolving the fluticasone        propionate in a solvent to thereby obtain a solution containing        the fluticasone propionate, whereby the solution is        substantially devoid of an additive; and spray drying the        solution, using a conventional spray drying apparatus and        technique, as described hereinabove.

According to an embodiment of this aspect of the present invention, theprocess is effected by providing a solution of fluticasone propionatewhereby the solution is consisting essentially of fluticasone propionateand solvent and spray drying this solution.

The fluticasone propionate used in the process described herein can beobtained commercially or prepared according to any of the knownprocedures described in the art and delineated supra. Optionally andpreferably, the fluticasone propionate can be prepared using the highlyefficient process described hereinabove.

Thus, according to a preferred embodiment of the present invention, thefluticasone propionate used in the process according to this aspect ofthe present invention is prepared by the process described hereinabove.Highly pure fluticasone propionate, having a purity as high as about99.8%, is therefore utilized herein.

As mentioned above, a critical component of the spray drying process,which is crucial for obtaining the desired final product is the liquidcarrier in which the drug is dissolved prior to the spray drying stage.This liquid carrier, also referred to herein and in the art as“feedstock”, is referred to herein interchangeably as a “solution” whichincludes the fluticasone propionate and a solvent.

The present inventors have now uncovered that by selecting anappropriate solvent in which the fluticasone propionate is dissolvedprior to the spray drying process, a powder having the desiredcharacteristics is obtained.

Appropriate solvents that are suitable for use in this context of thepresent invention thus include, without limitation, water, alcohols,ketones, acetates, ethers, nitrites and aprotic polar solvents.

More preferred solvents that are suitable for use in this context of thepresent invention include, low alcohols (having 2-8 carbon atoms) suchas, but not limited to, methanol, ethanol, n-propanol, isopropanol,n-butanol, and isobutanol; low ketones (having 2-8 carbon atoms) suchas, but not limited to, acetone, methyl ethyl ketone, diethyl ketone,methyl propyl ketone and methyl isobutyl ketone; low acetates (having2-8 carbon atoms) such as, but not limited to, ethyl acetate, n-propylacetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; lowethers (having 2-8 carbon atoms) such as, but not limited to, diethylether, diisopropyl ether, methyl tert-butyl ether and tetrahydrofurane;low nitrites such as, but not limited to, acetonitrile andpropionitrile; dimethylformamide (DMF), and any mixture thereof.

The presently most preferred solvents that are suitable for use in thiscontext of the present invention are low alcohols such as ethyl alcoholand isopropanol (also referred to herein as isopropyl alcohol), lowketones such as acetone and methyl ethyl ketone, and any mixturethereof.

When a mixture of two solvents is used, the ratio between the solventscan range from 1:99 to 99:1, and preferably ranges from 1:10 to 10:1,more preferably from 1:5 to 5:1, more preferably from 1:2 to 2:1 andmost preferably is 1:1.

The solution obtained by dissolving the fluticasone propionate in thesolvent described hereinabove is substantially devoid of an additive.

As used herein, the term “additive” describes a substance that istypically chemically inert and is added to another substance or amixture of substances, before, during or subsequent to applying acertain process on the substance or the mixture, and which is aimed atproviding the resulting product with certain physical and/or mechanicalcharacteristics. Additives are typically used, for example, in spraydrying processes, crystallization procedures, milling processes and thelike, and are aimed, for example, at modulating the solubility of asubstance during the process, enhancing the stability (mechanical orchemical) of a resulting product, modulating the viscosity and/or othermechanical parameters of a mixture, affecting the morphology of thesurface and crystal lattice of the resulting solids and the like.Exemplary additives that are commonly used in spray drying processesinclude, without limitation, lactose, polyvinyls such as PVA andpolyvinylpyrrolidone (PVP), phospholipid surfactants, nonionicdetergents, nonionic block copolymers, ionic surfactants andbiocompatible fluorinated.

By “substantially devoid of an additive” it is meant that the solutioncontains less than 1% of the additive, preferably less than 0.5% of theadditive and more preferably less than 0.1% of the additive, by weight.More preferably, the solution is completely devoid of an additive.

Circumventing the need to use additives, as taught herein, is beneficialsince the product obtained by the process described herein is highlypure, the need to remove the additives subsequent to obtaining thepowdered product is circumvented and the use of excessive chemicals isavoided, hence formulating cost is reduced.

Dissolving the fluticasone propionate in the solvent is typicallyperformed, according to preferred embodiments of the present inventioneither at room temperature or at elevated temperatures and is thuspreferably performed at a temperature that ranges from ambienttemperature to the reflux temperature of the selected solvent.Dissolving the fluticasone propionate in the solvent is thereforetypically carried out at a temperatures that ranges from 20° C. to 90°C., depending on the solvent used.

The concentration of the fluticasone propionate in the resultingsolution preferably ranges from about 1 gram of the fluticasonepropionate per 100 ml of the solution to about 50 grams of thefluticasone propionate to 100 ml of solution, more preferably from about1 gram of the fluticasone propionate per 100 ml of the solution to about10 grams of the fluticasone propionate to 100 ml of solution, and morepreferably is about 5 grams of the fluticasone propionate to 100 ml ofsolution.

The obtained hot solution is then charged on a conventional spray dryingapparatus, as exemplified in the Examples section that follows, andsubjected to a conventional spray drying procedure, as is furtherexemplified is the Examples section that follows.

According to a preferred embodiment of the process according to thisaspect of the present invention, the spray drying is carried out at thefollowing conditions: The outlet temperature of the spray dryer ispreferably set on a temperature greater than 60° C., and in some casesgreater than 80° C. and even greater than 85° C. The flow rate is set onbetween 20 m³/hour and 100 m³/hour, preferably between 40 m³/hour and 60m³/hour and more preferably is set on 50 m³/hour.

Other preferred parameters of the spray drying processes include aninlet temperature greater that ranges from 100° C. and 200° C.,preferably from 140° C. to 180° C., and more preferably is 160° C.

As is exemplified in the Examples section that follows, the processdescribed above, a powdered fluticasone propionate that has one or moreof the following characteristics is obtained:

-   -   an average particles size that ranges from about 1 micron to        about 10 micron and preferably from about 1 micron to about 5        microns;    -   a particle size distribution in which more than 90% of the        particles have a size of from about 1 micron to about 5 microns;    -   free flowing;    -   a substantially spherical particles shape; and    -   a substantial absence of an electrostatic charge.

In addition, and depending on the solvent used, the resulting powderedfluticasone propionate can be either crystalline or partially amorphous.Thus, for example, when a mixture of a low alcohol and a low ketone, asdescribed hereinabove, is used, a substantially crystalline powder offluticasone propionate is obtained, as is shown, for example, in FIG. 3.When a solvent including only acetone was used, partially amorphouspowder of fluticasone propionate was obtained, as is shown, for example,in FIG. 8.

Thus, the process according to this aspect of the present invention, isfurther beneficial as it enables, by appropriately selecting the solventused, to control the physical characteristics of the obtained powderedfluticasone propionate.

As is exemplified in the SEM micrograph presented FIG. 4, exemplaryparticles obtained by the process described herein have a spherical anda substantially ordered (crystalline) morphology. Further, it wasrecorded (data not shown) that particles devoid of electrostatic charge,namely uncharged particles, are obtained. As discussed hereinabove, suchproperties attribute to the free flowing of the powder and substantiallyreduce its tendency to agglomerate.

Indeed, it was observed that powdered fluticasone propionate prepared bythe process according to this aspect of the present invention ischaracterized as a free flowing powder.

The particle shape obtained by the process described herein is mostlyspherical, an attribute which contributes to the dry powder flow and theoverall desirable properties of the final product.

As presented in the Examples section that follows, the powderedfluticasone propionate obtained by the process, according to this aspectthe present invention, is desirably characterized by an average particlesize that ranges from about 1 micron to about 10 micron, and morepreferably from about 1 micron to about 5 micron.

Moreover, as is further presented in the Examples section that follows,the powdered fluticasone propionate obtained by the process according tothis aspect the present invention is further desirably characterized bya particle size distribution in which at least 90% and preferably atleast 95% of the particles in the powder have a size in the 1 to 10micron range. The powdered fluticasone propionate obtained by theprocess, according to this aspect the present invention, is furtherdesirably characterized by a particle size distribution in which atleast 85% and preferably at least 90% of the particles of the powderhave a size in the 1 to 5 micron range.

In addition, no more than 10% and preferably no more than 5% of theparticles in the powdered fluticasone propionate obtained by theprocess, according to this aspect the present invention, have a sizelarger than 5 microns and/or smaller than 1 micron.

Furthermore, as is further demonstrated in the Examples section thatfollows, in certain embodiments of the process according to the presentinvention, about 50% of the particles of the obtained powderedfluticasone propionate have a particle size which ranges from about 2microns to about 3 microns. Such a particles size distribution istypically obtained when a mixture of a low alcohol and a low ketone isused and the powder has a crystalline morphology.

In other embodiments of the process according to the present invention,about 50% of the particles of the obtained powdered fluticasonepropionate have a particle size which ranges from about 3 microns toabout 5 microns. Such a particles size distribution is typicallyobtained when a low ketone is used and the powder has a partiallyamorphous morphology.

The effect of the solvent used on the particles size and sizedistribution further emphasize the ability to control the physicalcharacteristics of the obtained powder, while using the processdescribed herein.

As one of the important traits of a powdered form of a pharmaceuticallyactive agent designed for delivery to the respiratory tract is a narrowparticle size distribution, the process according to this aspect of thepresent invention successfully achieves this attribute, as is detailedhereinabove and is further demonstrated in the Examples section thatfollows.

The process described herein is highly efficient, simple to perform andcan be readily scaled-up for industrial manufacture of a powderedfluticasone propionate. The powdered fluticasone propionate obtained bythis process is, as is detailed hereinabove, characterized by propertieswhich renders it highly suitable for use for administration byinhalation.

Thus, according to an additional aspect of the present invention thereis provided a powdered fluticasone propionate having one or more of thefollowing characteristics: an average particles size that ranges fromabout 1 micron to about 10 micron and preferably from about 1 micron toabout 5 microns; a particle size distribution in which more than 90% ofthe particles have a size of from about 1 micron to about 5 microns;free flowing; a substantially spherical particles shape; and asubstantial absence of an electrostatic charge, as is detailedhereinabove, and which can be either crystalline or partially amorphous,as is detailed hereinabove.

As discussed in detail hereinabove, the powdered fluticasone propionatedescribed herein can be beneficially incorporated in a pharmaceuticalcomposition and particularly is a pharmaceutical composition that isformulated fro admisnitration by inhalation.

Thus, according to still an additional aspect of the present inventionthere are provided pharmaceutical compositions that are formulated foradministration by inhalation. Each of these pharmaceutical computationsincludes, as an active ingredient, any of the powdered fluticasonepropionate described in this and other aspects of the present invention.

Preferably, such pharmaceutical compositions are identified for use inthe treatment of a disorder in the respiratory tract, and particularlyof a respiratory inflammation associated with e.g., asthma, andperennial rhinitis.

Each of the powdered fluticasone propionate described herein, either perse or as a part of the pharmaceutical compositions described herein, canbe further incorporated in a medical device designed for delivering anactive agent to the respiratory tract.

As is described hereinabove, exemplary devices that are designed fordelivering an active agent to the respiratory tract includes inhalers,whereby the most commonly used inhalers are a metered-dose inhaler (MDI)and a dry powder inhaler (DPI).

Thus, according to an embodiment of the present invention there isprovided a metered-dose inhaler that comprises a powdered fluticasonepropionate as described herein.

According to another embodiment of the present invention there isprovided a dry powder inhaler that comprises a powdered fluticasonepropionate as described herein.

Additional objects, advantages, and novel features of the presentinvention will become apparent to one ordinarily skilled in the art uponexamination of the following examples, which are not intended to belimiting. Additionally, each of the various embodiments and aspects ofthe present invention as delineated hereinabove and as claimed in theclaims section below finds experimental support in the followingexamples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions, illustrate the invention in a non limiting fashion.

Experimental Methods:

HPLC analyses were performed on a Hewlett Packard's HP 1050 HPLCapparatus, equipped with a Spherisorb ODSI column (5p, 250×4.6 mm) and aUV detector operated at 240 nm. Analyses conditions were as follows:Mobile phase: 42% 0.02 M ammonium dihydrogen phosphate buffer, pH=3.5,14% acetonitrile and 44% methanol; Flow rate=1.5 ml/minute; Injectionvolume: 20 μl; Oven Temp.=25° C.; Run Time=twice the retention time offluticasone propionate.

The dihydrogen phosphate buffer was prepared as follows: about 2.3 gramsof ammonium dihydrogen phosphate were placed in a 1000 ml volumetricflask, dissolved in water and volume was completed to 1000 ml withwater. pH was adjusted to 3.5 with phosphoric acid.

X-ray diffraction data were acquired using a PHILIPS X-raydiffractometer model PW1050-70 set at 40 kV, 28 mA, using 1.54178 Å(K_(α)), diversion slit of 1°, receiving slit of 0.2 mm, scattering slitof 1° and a graphite monochromator.

Spray drying was performed on a mini spray dryer by Buchi model B-190,with heater set to 1.8 KW to afford a temperature range of 40-220° C.,and an evaporation rate of approximately 1500 ml per hour.

Particle size was measured on a dynamic light scattering device byMalvern model Mastersizer 2000, using a measuring range of 0.02-2000 μm,accuracy level of 1% at the median, helium neon laser as a red lightsource, and solid state light source as a blue light source.

Particle size distributions are presented as the average particle sizeof specified percentiles, including the flanking 0.1 and 0.9 quantilesand the median 0.5 quantile of the overall particle size distributionversus volume curve.

Milling was carried out using ISOPAK SuperJet Mill, produced by APTM,equipped with grinding chamber of 8″ diameter having capacity of about1000 grams per hour.

Example 1 Preparation of highly pure fluticasone propionate

Ten (10) grams of(6S,9R,10S,11S,13S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioicS-acid (Compound I) and 50 ml acetonitrile were placed in a 200 ml glassautoclave vessel and the resulting mixture was stirred. Six (6) ml ofwater and 5.6 ml of diisopropylethylamine were added to the vessel whilestirring. The reaction mixture was heated to a temperature of about 50°C. and was stirred for 15 minutes, to afford a clear yellow solution.

3.2 grams of chlorofluoromethane were bubbled through a dip-pipe intothe stirred mixture and the autoclave was sealed. A pressure of about0.5 bar was developed while the mixture was heated for a period of 5hours. During the reaction, a suspension was produced. Thereafter thevent of the autoclave was opened and the mixture was cooled to roomtemperature. The mixture was stirred at room temperature for additional16 hours. The obtained suspension was cooled to 5° C. and was stirredfor 1 hour. The obtained solid product was filtered, washed with coldacetonitrile and dried at 60° C. to afford 8.4 grams of fluticasonepropionate (80% yield), having a purity of 99.8% as determined by HPLC.

Recrystallization was performed by dissolving 6.4 grams of fluticasonepropionate in a solvent mixture of 130 ml acetone and 60 ml isopropanolwhile mixing. The solution was heated to 30-35° C., about 0.6 gram ofactivated carbon was added hereto and mixing was continued for abouthalf an hour. The solution was then concentrated under reduced pressure,followed by cooling the resulting mixture to 10-15° C. for about anhour. The obtained precipitate was filtered off, washed twice withisopropanol and dried for 8 hours under vacuum to obtain 5.7 grams ofrecrystallized fluticasone propionate (89% yield).

Examples 2-10

Using the exemplary process described in Example 1 above, a series ofents with varying amounts of water were performed. The results are izedin Table 1 below: TABLE 1 Weight percents of added water (relative tothe Purity after Example weight of Compound I) Yield PurityCrystallization 2  0% 61 99.52 99.52 3  5% 55 99.56 99.62 4 10% 62 99.6699.63 5 20% 80 99.80 99.76 6 40% 75 99.50 99.58 7 60% 80 99.36 99.57 880% 78 99.26 99.61 9 100%  81 99.50 99.56 10 200%  85 99.19 99.53

Example 11 Purification of Compound I

Fifty (50) ml of a 5% sodium carbonate solution and 25 ml of ethylacetate were placed in a 250 ml reaction vessel equipped with a magneticstirrer. Five grams of Compound I were added to the vessel and thereaction mixture was stirred at room temperature for a period of about45 minutes, to afford a clear biphasic solution. The two layers werethen separated by means of a separating funnel and the aqueous layer wascooled to about 12° C. A solution of 4.1 ml of 32% HCl and 4.1 ml ofwater was added stepwise and the pH was adjusted to 1-2. The resultingsuspension was stirred for 30 minutes at about 12° C. The resultingsolid was filtered, washed with cold water until the washing solutionshowed a neutral pH, and dried at 60° C. in an air oven to yield 4.0grams of Compound I (80% yield) having a purity of 95.7% as determinedby HPLC.

Example 12

1000 grams of pure fluticasone propionate, prepared as describedhereinabove, were loaded onto an air-jet milling device equipped withgrinding chamber of 8″ diameter. The device was operated for about 60minutes.

FIG. 1 presents a SEM micrograph of the particles obtained by thismilling procedure and clearly shows the irregular jaggedly shapedparticles obtained. It is assumed that such a particles shape wasobtained as a result of the mechanical force applied against the crystallattice forces in this technique. Application of such a mechanical forcefurther leads to a reduction of the substance crystallinity, and to anincrease in activated surface and surface area, as compared with thenon-milled crystalline substance. In addition, the obtained particleshad unsatisfactory size distribution. Thus, it was found that theobtained product contained either too many oversized particles, too manyundersized particles or both (data not shown). In addition, it wasobserved that the product tended to accumulate a considerable amount ofelectrostatic charge and therefore exhibited a high tendency toagglomerate.

Example 13

Five grams of pure fluticasone propionate, prepared as describedhereinabove, were dissolved in 100 ml of a 1:1 mixture of isopropanoland methyl ethyl ketone at 60° C., and kept at that temperature untilcomplete dissolution was observed. The hot solution was then transferredinto the spray dryer at an outlet temperature of 87° C. and flow of 50m³/h.

The resulting solid was a free flowing crystalline powder which did notexhibit a tendency to agglomerate.

FIG. 2 presents the results of a light scattering device measurement ofthe particle size distribution. As can be seen in FIG. 2, the particlesize distribution was found to be 0.95μ in the 0.1 quantile; 2.21μ inthe 0.5 quantile; 4.23μ in the 0.9 quantile; and 4.96μ in the 0.95quantile.

FIG. 3 presents the X-ray power diffraction pattern of the resultingpowder. As is clearly shown in FIG. 3, the XRD pattern of the obtainedpowder is spiky and thus indicates a crystalline morphology of the finalproduct.

FIG. 4 presents a SEM micrograph of the obtained powder. As can be seenin FIG. 4, the particles are of regular spherical shape and have smoothsurface. Comparing the SEM micrograph presented in FIG. 4 (showing thefluticasone powder prepared according to the present embodiments) tothat presented in FIG. 1 (showing the fluticasone powder prepared by airjet milling) clearly shows the superior shape and morphology of theparticles obtained by the process of the present invention.

In addition, the product obtained in this process did not exhibit anystatic electricity and further did not exhibit any tendency toagglomerate.

Example 14

Five grams of pure fluticasone propionate were dissolved in 100 ml of a1:1 mixture of isopropanol and acetone at 60° C., and kept at thistemperature until complete dissolution was observed. The hot solutionwas then transferred into the spray dryer at an outlet temperature of64° C. and flow of 50 m³/h. 64° C.

The resulting solid was obtained as a free flowing crystalline powderwhich did not exhibit a tendency to agglomerate.

FIG. 5 presents the results of a light scattering device measurement ofthe particle size distribution. As can be seen in FIG. 4, the particlesize distribution was found to be 0.96μ in the 0.1 quantile; 2.14μ inthe 0.5 quantile; 4.36μ in the 0.9 quantile; and 5.27μ in the 0.95quantile.

Example 15

Five grams of pure fluticasone propionate were dissolved in 100 ml of a1:1 mixture of ethanol and methyl ethyl ketone at 60° C., and kept atthis temperature until complete dissolution was observed. The hotsolution was then transferred into the spray dryer at an outlettemperature of 87° C. and flow of 50 m³/h. 64° C.

The resulting solid was obtained as a free flowing crystalline powderwhich did not exhibit a tendency to agglomerate.

FIG. 6 presents the results of a light scattering device measurement ofthe particle size distribution. As can be seen in FIG. 6, the particlesize distribution was found to be 1.06μ in the 0.1 quantile; 2.67μ inthe 0.5 quantile; and 5.95μ in the 0.9 quantile.

Example 16

Five grams of pure fluticasone propionate were dissolved in 100 ml ofacetone at 50° C., and kept at this temperature until completedissolution was observed. The hot solution was then transferred into thespray dryer at an outlet temperature of 80° C. and flow of 50 m³/h.

FIG. 7 presents the results of a light scattering device measurement ofthe particle size distribution. As can be seen in FIG. 7, the particlesize distribution was found to be 1.90μ in the 0.1 quantile; 4.11μ inthe 0.5 quantile; and 8.40μ in the 0.9 quantile.

FIG. 8 presents the X-ray power diffraction pattern of the resultingpowder. As can be seen in FIG. 8, the XRD pattern of the powder is arelatively continuous and smooth curve, indicating a low level of acrystalline morphology of the final product.

Thus, the resulting solid was obtained as a partially amorphous powderhaving a particle size of less than 10 microns.

The various parameters used in the exemplary processes according to thepresent invention described in Examples 13-16 hereinabove and theireffect on the characteristics of the resulting powder are summarized inTable 2 below. TABLE 2 Solvent or solvent Example mixture Processparameters Powder characteristics 13 1:1 mixture of Dissolving at 60° C.and Free flowing crystalline powder isopropanol and maintaining the thatdoes not tend to agglomerate. methyl ethyl ketone temperature untilcomplete Particle size median: 2.21 microns dissolution. Hot solutionParticle size distribution: was fed into the spray D(v, 0.1) = 0.95μ;D(v, 0.5) = 2.21μ; dryer at outlet temperature D(v, 0.9) = 4.23μ; D(v,0.95) = 4.96μ. of 87° C. and flow of 50 m³/h 14 1:1 mixture ofDissolving at 60° C. and Free flowing crystalline powder isopropanol andmaintaining the that does not tend to agglomerate. acetone temperatureuntil complete Particle size median: 2.14 microns; dissolution. Hotsolution Particle size distribution: was fed into the spray D(v, 0.1) =0.96μ; D(v, 0.5) = 2.14μ; dryer at outlet temperature D(v, 0.9) = 4.36μ;D(v, 0.95) = 5.27μ of 64° C. and flow of 50 m³/h 15 1:1 mixture ofDissolving at 60° C. and Free flowing crystalline powder ethanol andmethyl maintaining the that does not tend to agglomerate. ethyl ketonetemperature until complete Particle size median 2.67 microns;dissolution. Hot solution Particle size distribution: was fed into thespray D(v, 0.1) = 1.06μ; D(v, 0.5) = 2.67μ; dryer at outlet temperatureD(v, 0.9) = 5.95μ. of 87° C. and flow of 50 m³/h 16 Acetone Dissolvingat 50° C. and Partially amorphous powder. maintaining the Particle sizemedian 4.10 microns; temperature until complete Particle sizedistribution: dissolution. Hot solution D(v, 0.1) = 1.90μ; D(v, 0.5) =4.10μ; was fed into the spray D(v, 0.9) = 8.39μ D(v, 0.95) = 9.86μ.dryer at outlet temperature of 80° C. and flow of 50 m³/h

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

1. A process of preparingS-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate(fluticasone propionate), the process comprising: providing6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; reacting said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid with a halofluoromethane in the presence of an organic solvent,water and a base, to thereby obtain a reaction mixture containingfluticasone propionate; and isolating the fluticasone propionate fromsaid reaction mixture, thereby obtaining the fluticasone propionate. 2.The process of claim 1, wherein said halofluoromethane is selected fromthe group consisting of chlorofluoromethane, bromofluoromethane andiodofluoromethane.
 3. The process of claim 1, wherein said organicsolvent is selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofurane, acetonitrile and any mixture thereof.
 4. Theprocess of claim 1, wherein said base is a tertiary alkylamine.
 5. Theprocess of claim 1, wherein an amount of said water ranges from about 1weight percent to about 200 weight percents of the weight of said6α,9α-difluoro-11β-hydroxy-17β-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid.
 6. The process of claim 5, wherein an amount of said water rangesfrom about 40 weight percents to about 70 weight percents of the weightof said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid.
 7. The process of claim 1, further comprising, prior to saidreacting, purifying said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid.
 8. The process of claim 7, wherein said purifying comprises:providing a solution of said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid and an organic solvent; contacting said solution with an aqueoussolution containing a base, to thereby provide an aqueous solutioncontaining a base addition salt of said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; isolating said aqueous solution containing said base additionsalt; converting said base addition salt into said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; and isolating said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid, to thereby provide a purified6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid.
 9. The process of claim 1, wherein said fluticasone propionate hasa purity that equals to or is greater than 99%.
 10. The process of claim9, wherein said fluticasone propionate has a purity that equals to or isgreater than 99.5%.
 11. The process of claim 1, further comprising,subsequent to said isolating: providing a powdered fluticasonepropionate.
 12. The process of claim 11, wherein providing said powderedfluticasone propionate comprises: subjecting said fluticasone propionateto spray drying.
 13. The process of claim 12, wherein said spray dryingcomprises: providing a solution containing fluticasone propionate and asolvent; and spray drying said solution.
 14. The process of claim 13,wherein said solution is substantially devoid of an additive. 15.Fluticasone propionate prepared by the process of claim
 1. 16. Powderedfluticasone propionate prepared by the process of claim
 13. 17.Fluticasone propionate having a purity that equals to or is greater than99%.
 18. The fluticasone propionate of claim 17, having a purity thatequals to or is greater than 99.5%.
 19. A process of preparing apowdered fluticasone propionate, the process comprising: providingfluticasone propionate; dissolving said fluticasone propionate in asolvent to thereby obtain a solution containing said fluticasonepropionate, said solution being substantially devoid of an additive; andspray drying said solution, thereby obtaining the powdered fluticasonepropionate.
 20. The process of claim 19, wherein providing saidfluticasone propionate comprises: providing6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; reacting said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid with a halofluoromethane in the presence of an organic solvent,water and a base, to thereby obtain a reaction mixture containingfluticasone propionate; and isolating the fluticasone propionate fromsaid reaction mixture, thereby obtaining the fluticasone propionate. 21.The process of claim 19, wherein the powdered fluticasone propionate hasat least one characteristic selected from the group consisting of: anaverage size that ranges from about 1 micron to about 10 micron; freeflowing; a substantially spherical particles shape; and a substantialabsence of an electrostatic charge.
 22. The process of claim 21, whereinthe powdered fluticasone propionate is substantially crystalline. 23.The process of claim 21, wherein the powdered fluticasone propionate ispartially amorphous.
 24. The process of claim 21, wherein said averageparticle size ranges from about 1 micron to about 5 microns.
 25. Theprocess of claim 24, wherein a particle size of at least 90 percents ofthe particles of the powdered fluticasone propionate ranges from 1 to 5microns.
 26. The process of claim 22, wherein a particle size of about50 percents of the particles of the powdered fluticasone propionateranges from about 2 microns to about 3 microns.
 27. The process of claim23, wherein a particle size of about 50 percents of the particles of thepowdered fluticasone propionate ranges from about 3 microns to about 5microns.
 28. The process of claim 19, wherein said solvent is selectedfrom the group consisting of an alcohol, a ketone and a mixture thereof.29. The process of claim 28, wherein said alcohol is selected from thegroup consisting of ethanol and isopropanol.
 30. The process of claim28, wherein said ketone is selected from the group consisting of acetoneand methyl ethyl ketone.
 31. The process of claim 28, wherein a ratiobetween said alcohol and said ketone in said mixture is about 1:1. 32.The process of claim 19, wherein said spray drying is performed at anoutlet temperature greater than 60° C.
 33. The process of claim 32,wherein said spray drying is performed at a flow of about 50 m³/hour.34. A powdered fluticasone propionate prepared by the process of claim19.
 35. A pharmaceutical composition being formulated for administrationby inhalation, comprising the powdered fluticasone propionate of claim34.
 36. A powderedS-fluoromethyl-6α9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17p-carbothioate(fluticasone propionate) being characterized by at least onecharacteristic selected from the group consisting of: an averageparticle size that ranges from about 1 micron to about 10 micron; freeflowing; a substantially spherical particles shape; and a substantialabsence of an electrostatic charge.
 37. The powdered fluticasonepropionate of claim 36, being substantially crystalline.
 38. Thepowdered fluticasone propionate of claim 36, being partially amorphous.39. The powdered fluticasone propionate of claim 36, wherein saidaverage particle size ranges from about 1 micron to about 5 microns. 40.The powdered fluticasone propionate of claim 39, wherein a particle sizeof at least 90 percents of the particles of the powdered fluticasonepropionate ranges from 1 to 5 microns.
 41. The powdered fluticasonepropionate of claim 37, wherein a particle size of about 50 percents ofthe particles of the powdered fluticasone propionate ranges from about 2microns to about 3 microns.
 42. The powdered fluticasone propionate ofclaim 38, wherein a particle size of about 50 percents of the particlesof the powdered fluticasone propionate ranges from about 3 microns toabout 5 microns.
 43. A pharmaceutical composition being formulated foradministration by inhalation, comprising, as an active ingredient, thepowdered fluticasone propionate of claim
 36. 44. A process of purifying6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17α-thiocarboxylicacid, the process comprising: providing6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; providing a solution of said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid and an organic solvent; contacting said solution with an aqueoussolution containing a base, to thereby provide an aqueous solutioncontaining a base addition salt of said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; isolating said aqueous solution containing said base additionsalt; converting said base addition salt into said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid; and isolating said6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid, to thereby provide a purified6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylicacid.